Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance

Abstract

γδ T cells are considered to be innate-like lymphocytes that respond rapidly to stress without clonal selection and differentiation. Here we use next-generation sequencing to probe how this paradigm relates to human Vδ2neg T cells, implicated in responses to viral infection and cancer. The prevalent Vδ1 T cell receptor (TCR) repertoire is private and initially unfocused in cord blood, typically becoming strongly focused on a few high-frequency clonotypes by adulthood. Clonal expansions have differentiated from a naive to effector phenotype associated with CD27 downregulation, retaining proliferative capacity and TCR sensitivity, displaying increased cytotoxic markers and altered homing capabilities, and remaining relatively stable over time. Contrastingly, Vδ2+ T cells express semi-invariant TCRs, which are present at birth and shared between individuals. Human Vδ1+ T cells have therefore evolved a distinct biology from the Vδ2+ subset, involving a central, personalized role for the γδ TCR in directing a highly adaptive yet unconventional form of immune surveillance.

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

“…Vδ1 + γδ T cells have a more diverse TCR repertoire and have been associated with adaptive responses, especially against viruses such as CMV (54,55). In the present study, an increased proportion of circulating TNF/IFN-γ-producing Vδ2 + γδ T cells were found in IRAK4-deficient individuals; these most likely expanded as a result of the recurrent infections in these patients (8).…”

“…In humans, Vδ2 + γδ T cells have a semi-invariant TCR repertoire and rapidly expand and contribute to host defense against microbial infections (54,55). Vδ1 + γδ T cells have a more diverse TCR repertoire and have been associated with adaptive responses, especially against viruses such as CMV (54,55).…”

Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36-Mediated T Cell Responses

“…In addition, adoptive transfer T cells from lymph nodes rescued the skin inflammation in IL-36R −/− mice. Our findings with γδ T cells might better translate to humans because circulating Vγ9/Vδ2 and Vδ1 + γδ T cell populations in human blood have been increasingly recognized to participate in the immune response to pathogens (Davey et al, 2017; Ravens et al, 2017). Finally, in response to a deeper subcutaneous S. aureus challenge in mice, adipocytes produced the antimicrobial peptide CRAMP to promote bacterial clearance, but a role for IL-36 or other IL-1 family members was not evaluated (Zhang et al, 2015).…”

Clonal expansion shapes the human Vδ1T cell receptor repertoire

“…In a recent issue of Nature Communication, Davey et al 2 used amplicon rescued multiplex (ARM)-PCR and next-generation sequencing to investigate the clonal selection of a γδ TCR repertoire that was negative for the Vδ2 chain in healthy adults and in cord blood. As expected, in all individuals, the Vδ2 − γδ T cell population was dominated by Vδ1 + T cells paired with diverse Vγ chains and displaying a mixed terminally differentiated effector memory (CD27 − CD45RA + ) or naive (CD27 + CD45RA + ) phenotype.…”

“…To investigate how the Vδ1 + TCR repertoire differed in early life, Davey et al 2 conducted comparable TCR repertoire analyses on the Vδ1 + population obtained from cord blood. Vδ1 + cells dominate the cord blood γδ repertoire and express Vδ1 paired with diverse Vγ regions.…”